Plant-based Penn research improves hemophilia treatment

By Katherine Unger Baillie

Hemophilia is a rare but potentially dangerous disease. People with the condition produce very low levels of clotting factor, the proteins in blood that stop bleeding and help begin the healing process.

Individuals with severe forms of hemophilia can suffer from prolonged bleeding, even from minor wounds, and serious internal bleeding. To avoid these problems, one option is to receive regular injections of clotting factor. But about one-quarter of patients receiving these treatments develop antibodies—called inhibitors—against the infused clotting factor, a serious complication that can make treating future bleeding episodes very challenging.

But what if a patient’s immune system could be “taught” to tolerate the clotting factor infusions? That’s what Henry Daniell, a professor in the departments of biochemistry and pathology and director of translational research at Penn’s School of Dental Medicine, has accomplished in a new study, published online in the journal Blood.

Hemophilia, an inherited disorder, usually occurs in males (with rare exceptions). About one in 5,000 males are born with hemophilia each year.

Working with colleagues, Daniell relied on his plant-based drug-delivery platform, which uses genetically engineered plants to produce biotherapeutic proteins. To promote tolerance to the clotting factor VIII (FVIII)—the protein that is depleted in people with hemophilia A—they fused genes that encode parts of FVIII to the gene for cholera toxin, a protein that is able to cross the intestinal wall and may help promote certain types of immune responses.

The researchers introduced these fused genes into tobacco plant chloroplasts, grew the plants, ground them up, and suspended them in a solution. They fed the solutions with the modified plant material to a group of mice with hemophilia A over two months, and fed another group of mice a solution with normal plant material. After giving the mice infusions of FVIII, the rodents fed normal plant solution formed high levels of inhibitors, while the group that was fed the modified plant material formed much lower levels of inhibitors.

Not only could the researchers prevent inhibitor formation, they could reverse it, as well. After feeding the modified plant material to mice that had already developed inhibitors, Daniell’s team found that the mice’s inhibitor formation slowed and then reversed, decreasing three- to seven-fold over a few months compared to mice fed normal plant material.

Though other therapies exist to teach the immune system to tolerate clotting factors, Daniell believes this new finding offers a promising alternative.

“The only current treatments for inhibitor formation cost $1 million and are risky for patients,” Daniell says. “Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative.”

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